Rod vision in mammals is remarkably sensitive, allowing vision under conditions where few rods absorb photons. Additionally, rod vision extends over 8 orders of magnitude in light intensity above this threshold. The experiments described in this proposal are aimed at elucidating fundamental retinal mechanisms that allow both the discrimination of rod photoresponses from noise near visual threshold, and allow rod photoresponses to be transmitted to retinal ganglion cells through several parallel pathways over a wide range of light intensities. To accomplish these goals we propose to record light-evoked responses from rod photoreceptors and downstream retinal neurons (bipolar cells, amacrine cells, and ganglion cells) of wild-type and several transgenic mouse strains. We aim to answer several fundamental questions about how rod photoresponses are processed and parsed within the retinal circuitry. First, we propose to identify the limiting source of noise in the rod photoreceptors that sets visual threshold by utilizing mouse models with reduced rod noise. We will compare how reduced noise influences the detection of single photon responses, and how it influences the behavioral threshold for seeing. The limiting noise in rods reflects a key control point within rod phototransduction that sets absolute visual threshold. Second, we propose to characterize the properties of rod-driven signals in the primary rod pathway and determine how sensitivity is modulated during adaptation to background light. Finally, we propose to characterize how cone bipolar cells integrate rod-driven signals generated by the primary and secondary rod pathways, along with cone-driven signals, using mice where either rod or cone phototransduction has been silenced. These experiments will allow us to dissect how rod-driven signals in many parallel pathways combine with cone-driven signals to define the dynamic range of rod vision. Our long-term goal is to provide a comprehensive understanding of the mechanisms that control the transmission of rod-driven signals to higher visual centers. This work is aligned with the objectives of the Retinal Diseases Program of the NEI "to use molecular and physiological approaches to identify post photoreceptor neural components of adaptation", which will be key to understanding the pathophysiology associated with deficits in rod vision. PUBLIC HEALTH RELEVANCE: In mammals rod vision is not only sufficiently sensitive to encode few photon absorptions in the array of rods near visual threshold, but can also operate up to light levels where its function is merged with the cone system. This wide dynamic range, encompassing 100,000,000-fold differences in light intensity, is the result of physiological mechanisms and multiple rod retinal pathways that enhance the properties of signals with respect to noise when background light levels are low, but can also adapt to the mean illumination as background light levels increase. This proposal is aimed at elucidating the functional properties of the rod circuitry that produce this dynamic range, and in understanding how these contribute to rod vision.